DESCRIPTION: Objective: Fibrous tissues of the musculoskeletal system are plagued by their poor intrinsic healing capacity. In this proposal, we focus on the knee meniscus, a tissue critical for proper load transfer, and for which current repair strategies do not restore function. To address this clinical need, we have devised a novel strategy employing anisotropic biodegradable composite nanofibrous scaffolds that serve as an inter- positional device and enhance meniscus repair. The objective of this study is to develop nanofibrous scaffolds capable of releasing multiple agents over different temporal scales, and thus, positively impact the entire healing process. Research Design: This proposal will utilize a novel class of composite nanofibrous scaffolds (developed during the first funding cycle) that have varying degradation profiles and release kinetics of bioactive agents targeted to different phases of healing and repair. These release profiles will be tuned to first 'enable' repair by rapidly and locally degrading the dense extracellular matrix at the injury site to allow cell migration and new tissue formation. Second, these scaffolds will selectively recruit progenitor cells to the wound interface, to accelerate and sustain the repair process. Finally, the scaffold will provide biochemical factors over a longer-term to 'direct' cell phenotype and promote matrix production. The synergistic interactions of these different adjuvants to repair will be investigated in a large animal meniscus defect model. Methodology: We will develop and characterize composite nanofibrous scaffold systems that permit release of factors from the fibers themselves or from encapsulated microspheres. This novel scaffolding technology allows for the inclusion of several fiber populations with different degradation profiles and for the release of multiple bioactive factors with varying temporal release profiles. Scaffolds will be utilized in a model of meniscus repair in adult sheep and compared to suture repair controls at early (2, 4, and 8 weeks) and longer term (16 and 48 week) time points. Evaluation criteria will include meniscus and cartilage histology, micro-computed tomography, and mechanical properties. Findings: We will develop composite nanofiber-based engineered scaffolds to enhance meniscus repair in an ovine model. We will show enhanced cellularity and integration with local matrix degradation at the injury site. We will also show increased recruitment of progenitor cells as well as improved matrix production with staged biofactor delivery. The synergistic effects of these treatments will be assessed relative to the current standard of care. Clinical Relationships: If successful, these studies and new technologies will set the stage for clinical translation and treatment of human meniscal pathology. These novel scaffolds can be directly utilized in clinical procedures to enhance meniscus repair. Impact/Significance: The proposed research is highly relevant to the mission of the Veterans Health Administration since it will advance the health of veterans suffering from meniscus injuries resulting from military trauma, injury or from degenerative diseases. If successful, the proposed therapy will improve the quality of life of such individuals.